Review articleThe p38 signal transduction pathway Activation and function
Introduction
The response of cells to extracellular stimuli is in part mediated by a number of intracellular kinase and phosphatase enzymes [1]. The mitogen-activated protein (MAP) kinases are members of discrete signalling cascades, which are focal points for diverse extracellular stimuli, and function to regulate fundamental cellular processes. Four distinct subgroups within the MAP kinase family have been described. These include (1) extracellular signal-regulated kinases (ERKs), (2) c-jun N-terminal or stress-activated protein kinases (JNK/SAPK), (3) ERK5/big MAP kinase 1 (BMK1), and (4) the p38 group of protein kinases. Within this area of research, the activation of ERKs has been extensively described and characterised as a central component of the signal transduction pathways, stimulated by growth-related stimuli 2, 3. The JNK group of protein kinases are activated in response to a number of cellular stresses, including high osmolarity and oxidation [4]. The ERK5/BMK1 MAP kinase signalling pathway regulates serum-induced early gene expression [5]. The p38 group kinases have been found to be involved in inflammation, cell growth, cell differentiation, the cell cycle, and cell death [6]. It is clear, then, that the p38 pathway shares many similarities with the other MAP kinase cascades. The purpose of this review, however, is to highlight the unique characteristics of the p38 group of kinases, the components of this kinase cascade as well as the activation of this pathway and the biological consequences of its activation.
Section snippets
Properties of the p38 group of MAP kinase members
p38α (or simply p38) was first isolated as 38-kDa protein, which was rapidly tyrosine phosphorylated in response to LPS stimulation 7, 8. Molecular cloning of the protein revealed that it is an MAP kinase family member [8]. p38 (termed RK and p40) was identified as an upstream kinase of MAP kinase-activated protein kinase-2 (MAPKAPK-2 or M2) in IL-1 or arsenite-stimulated cells 9, 10. p38 was also purified and its cDNA cloned as a molecule that binds pyridinyl imidazole derivatives (which
Extracellular stimuli
p38 homologues have been identified and cloned in both low and high eukaryotic species, including fly, frog, and yeast 10, 28, 29, 30. The Hog1 pathway [29] in budding yeast and the Spc1/Sty1 pathway in fission yeast [30] are believed to share an ancestral gene with p38 group kinases. Their role has been implicated in osmoregulation, responses to extracellular stress stimuli, and cell-cycle events 29, 30, 31. Mammalian p38s are also activated by environmental stresses 8, 9, 10, 11, 32. Since
Downregulation of the p38 signalling pathway
Under physiological conditions, MAP kinase activation is often transient. Because the level of MAP kinases never changes throughout the course of stimulation, dephosphorylation by phosphatases would seem to play a major role in the downregulation of MAP kinase activity. A group of dual phosphatase has been identified and cloned. MAP kinase phosphatase (MKP)-1 (or CL100/3CH134) is the archetypal member of this gene family and has activity for several MAP kinases, such as ERK, JNK, and p38 [84].
Protein kinase substrates of p38
MAP kinase-activated protein kinase 2 (MAPKAP-K2 or M2) was the first identified p38α substrate. In vitro phosphorylation of M2 by p38α activates M2. In vivo activation is inhibited by SB203580, a specific inhibitor of p38α and p38β 9, 10, 95. Subsequently, a closely related protein kinase, M3 (or 3pk), was also found to be a substrate of p38α [95]. Moreover, activated M2 and 3 phosphorylate various substrates including small heat shock protein 27 (HSP27) [96], lymphocyte-specific protein 1
Genes regulated by the p38 pathway
The use of inactive and constitutively active mutants of MKK3 and 6 as well as the use of the p38 inhibitor, SB203580, has greatly elucidated how p38 functions to regulate different genes. The expression of many cytokines, transcription factors, and cell surface receptors was found to be coordinated by p38. Table 3 summarises the genes that were reported to be regulated by the p38 pathway. In the future, the full identification of p38 regulated genes will be a great help to the understanding of
p38 and inflammation
Evidence to support the importance of the p38 pathway in inflammation comes from several sources. The activation of the p38 pathway plays an essential role in: (1) production of proinflammatory cytokines such as IL-1β, TNF-α and IL-6 [119]; (2) induction of enzymes such as COX-2 [120], which controls connective tissue remodelling in pathological condition; (3) expression of an intracellular enzyme such as iNOS 121, 122, which regulates oxidation; (4) induction of adherent proteins such as
Discussion
Due to the brevity of this review, it is impossible to cover all the research done on the p38 signal cascade. However, certain encompassing conclusions may be drawn concerning how p38 operates as a signal transduction mediator. p38 is activated by both stress and mitogen stimuli in a cell specific manner. The p38 group of kinases can directly or indirectly target various proteins to control transcription and translation. This kinase also activates other kinases and consequently regulates
Acknowledgements
This is publication no. 12597-IMM from the Department of Immunology of The Scripps Research Institute, La Jolla, California. This work was supported by grants from the U.S. Public Health Service (National Institutes of Health grant nos. GM51470 and AI41637 to J.H.). K.O. is a Research Fellow of the Japan Society for the Promotion of Science. J.H. is an established investigator of the American Heart Association. We thank Janet V. Kuhns for excellent secretarial assistance.
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